Management of mental health issues in the post-transplant setting can be difficult given the potential for medication related neurotoxicity. The lack of established guidelines in this area further compounds this difficulty. The current report details the course of patient with stable bipolar affective disorder prior to renal transplantation, who developed de novo psychosis post-transplantation as an adverse effect of her tacrolimus therapy. The patient was unable to take her usual oral immunosuppressants due to the severity of her psychosis and she eventually required alemtuzumab parenterally as rescue therapy from rejection. This case highlights the diagnostic and therapeutic challenges when dealing with transplant recipients with significant psychosis.